Академический Документы
Профессиональный Документы
Культура Документы
E
pital Wales, Cardiff, Wales
8
Department of Family & Community czema affects nearly 1 in 5 people in the United States and the
Medicine and Dalla Lana School of Public United Kingdom and can significantly impair quality of life.1-3 The
Health, North York General Hospital, Uni- condition is characterized by exacerbations and remissions, and
versity of Toronto, Toronto, Canada in the United Kingdom it is estimated that children experience approxi-
mately 2.2 million eczema flares (worsening of their eczema) a year.4 The
cause of flares, however, remains uncertain.5 There are no published data
on how eczema flares are managed in primary care, but it has been esti-
mated that 40% are treated with topical antibiotics, and our unpublished
Conflicts of interest: authors report none.
pilot study suggests that 54% of children with eczema aged 5 years or
CORRESPONDING AUTHOR younger are given antibiotics in the course of a year.4 Widespread use of
Nick A. Francis antimicrobials is a key contributor to the development of antimicrobial
Division of Population Medicine, School of resistance and exposes children to possible harms from adverse effects.6
Medicine, Cardiff University
Neuadd Meirionnydd, Heath Park, Cardiff, Staphylococcus aureus (S. aureus) can be isolated from lesional skin in about
CF14 4YS 70% of patients with eczema. The odds of colonization are nearly 20 times
francisna@cf.ac.uk those in people without eczema,7 and more severe eczema is associated
ANNALS O F FAMILY MED ICINE WWW.AN N FA MME D.O R G VO L. 15, N O. 2 MA RCH/A P R IL 2017
124
ANTIBIOTICS FOR EC ZEMA
with higher organism density.8 Despite the clear asso- study team were blinded to allocation. The oral anti-
ciation between eczema and the presence of S. aureus, biotics under evaluation were flucloxacillin (floxacillin)
however, there is uncertainty about what constitutes suspension (250mg/5mL) or erythromycin suspension
infection and when antibiotic treatments are likely to (250mg/5mL) for those with penicillin allergy. Parents
confer benefit.9 A 2010 update of a Cochrane review of were instructed to administer 2.5mL (125mg) 4 times
antimicrobial interventions for eczema found that most a day to participants aged 2 years or less and 5mL
relevant studies were small and of poor quality. None (250mg) 4 times a day to older participants for 7 days.
found meaningful clinical benefit from antimicrobial The topical antibiotic under evaluation was 2% fusidic
intervention despite reduction in the presence of S. acid cream, applied 3 times a day for 7 days. All place-
aureus, and the authors questioned the ongoing use of bos were matched according to taste and appearance.
antibiotics for eczema flares.10 All participants were also prescribed a topical cortico-
We set out to assess whether oral or topical anti- steroid: hydrocortisone 1% for the face and clobetasone
biotics, in addition to standard treatment with topical butyrate 0.05% (or equivalent) for other parts of the
corticosteroids, were more effective than placebo in body, and an emollient of their choice (excluding emol-
reducing subjective eczema severity in children with lients containing antimicrobials).
clinically infected eczema.
Data Collection
Research nurses conducted a baseline visit as soon as
METHODS possible and no later than 72 hours after a patient was
CREAM (Children with Eczema Antibiotic Manage- identified by a participating site. The baseline visit was
ment study) was a 3-arm, double-dummy, blinded, used to obtain consent, collect baseline data, and sup-
individually randomized controlled trial in ambulatory ply study medication. Baseline data collected included
care in the United Kingdom. demographics, duration of current flare, medication,
symptoms, temperature, signs of infection, and the
Participants outcome measures detailed below. Parents were asked
Children aged 3 months to 7 years were eligible if they to complete a 4-week daily diary of symptom severity
were consulting in a participating National Health Ser- (skin redness, cracking, soreness, itch, sleep distur-
vice (NHS) general practice or direct-access dermatol- bance, oozing or weeping, bleeding, and fever), adverse
ogy clinic for clinically infected eczema.11 Treating effects (nausea, vomiting, diarrhea, abdominal pain,
clinicians were asked to include patients whom they joint pains, and new rash), medication use, and consul-
believed to have infected eczema and were given guid- tations. Research nurses visited participants again at 2
ance that symptoms or signs suggestive of infection and 4 weeks and reviewed their medical records at 3
could include the following: months. At that point, parents of participants were also
eczema that is failing to respond to standard treat- asked to complete a postal questionnaire.
ment with emollients and/or mild-to-moderate topi- The primary outcome was the Patient Oriented
cal corticosteroids Eczema Measure (POEM) score at 2 weeks. POEM
a flare in the severity or extent of the eczema measures subjective eczema severity over the previous
weeping or crusting week and results in a score from 0 to 72, with higher
Children were excluded if they had recently used scores representing more severe eczema severity.12 The
potent or very potent topical corticosteroids or minimum clinically important difference for POEM is
antibiotics or if they had features of severe infec- about 3.13,14 Secondary outcomes were the Eczema Area
tion or significant comorbid illness (Supplemental and Severity Index (EASI),15 Infants Dermatitis Qual-
Appendix 1, available at http://www.AnnFamMed.org/ ity of Life instrument (IDQoL)16 for participants aged 3
content/15/2/124/suppl/DC1/). months to 4 years, Childrens Dermatology Life Qual-
ity Index (CDLQI)17 for participants aged 4 years to 8
Interventions years, Dermatitis Family Impact (DFI)18 instrument, and
Participants were randomized to 1 of 3 study arms: oral the Atopic Dermatitis Quality of Life (ADQoL) instru-
and topical placebos (the control group); oral antibi- ment.19 The weight of unused study medication (includ-
otic and topical placebo (the oral antibiotic group, or ing steroids) was measured at 2 weeks. The research
OA); or topical antibiotic and oral placebo (the topi- nurses collected swabs of the eczematous skin, throat
cal antibiotic group, or TA). Random allocation was and anterior nares at baseline and week 2, and the par-
undertaken by site pharmacies using block randomiza- ents were asked to do so again at 3 months. Baseline skin
tion with randomly chosen balanced block sizes of 6 or swabs were used to describe the prevalence of S. aureus
9. Participants, parents, and all other members of the found on participants eczematous skin, and baseline
ANNALS O F FAMILY MED ICINE WWW.AN N FA MME D.O R G VO L. 15, N O. 2 MA RCH/A P R IL 2017
125
ANTIBIOTICS FOR EC ZEMA
and follow-up swabs were used to identify antimicrobial comply with (adhere to) treatment, and is recom-
resistance in S. aureus and beta-hemolytic streptococci mended over per-protocol analyses.21
(Supplemental Appendix 2, available at http://www. Analyses were conducted using SPSS version 20
AnnFamMed.org/content/15/2/124/suppl/DC1/). (IBM Corp). The full trial protocol is available as a
supplementary file (Supplemental Appendix 4, avail-
Analysis able at http://www.AnnFamMed.org/content/15/2/124/
Our initial sample size calculation was based on a clini- suppl/DC1/). The study was approved by the National
cally important difference of 3 in POEM score and Research Ethics Service South Wales Ethics Commit-
a common standard deviation of 7. Using =0.025 tee (Reference: 12/WA/0180), and is registered with
and 90% power we determined that we required 137 the ISRCTN registry: 96705420.
participants per treatment group, giving a total of
411, or 517 when allowing 20% loss to follow-up. In
April 2014, we used the data from the first 69 partici- RESULTS
pants to revisit some of the parameters in the sample Ninety-four sites (90 general practices and 4 hospital
size calculation. Using the standard deviation from dermatology clinics) were opened between July 2013
the baseline POEM scores (5.3) and the correlation and November 2014, and of these, 33 (32 general prac-
between baseline and 2-week POEM scores (0.27) and tices and 1 dermatology clinic) recruited 1 or more
the same clinically important difference for POEM, we participants. Participating sites were slightly larger
found that 75 patients per group are required to reach than non-participating practices (mean practice list size
90% power, giving a total of 225 required for analysis. 9,452 vs 6,451), but there were no significant differ-
Continuing to allow 20% loss to follow-up resulted in a ences in number of partners, proportion of list aged 8
revised recruitment target of 282 participants. years or less, or proportion of children aged 8 years or
Our primary analyses were intention-to-treat less who have eczema.22
comparisons of week 2 POEM scores in each of the 2 One hundred thirteen participants were randomized
intervention groups with control, adjusted for baseline (Supplemental Appendix 5, available at http://www.
POEM scores using ANCOVA. Secondary analyses AnnFamMed.org/content/15/2/124/suppl/DC1/), which
were also carried out using ANCOVA. We used rules was less than the target sample size. Three participants
on missing data from the score questionnaire develop- had penicillin allergy, but none were randomized to the
ers (Supplemental Appendix 3, available at http://www. oral antibiotics group, so no participants received oral
AnnFamMed.org/content/15/2/124/suppl/DC1/). Daily erythromycin. There were no significant differences in
symptom scores were added to create a total daily baseline characteristics among the 3 groups (Table 1).
symptom severity score. Mean daily symptom scores More than 90% of participants had 1 or more classic
for each group were plotted and compared using area- signs of infection recorded by the recruiting clinician,
under-the-curve analyses. Medication use was calcu- and 70% had S. aureus isolated from a skin swab. Nurse
lated as the proportion between the number of doses/ baseline assessments (n=100) revealed that 30.0%,
applications recorded in the patient diary and the total 10.1%, 6.8%, and 53.0% had moderate or severe crust-
number of prescribed doses for that medication. Topical ing, weeping, pustules, and erythema respectively.
corticosteroids were classified as mild, moderate, potent, POEM scores were similar in the 3 groups at base-
or very potent using British National Formulary clas- line, and reduced (improved) in all 3 groups by 2 weeks
sification.20 Skin swab results were expressed as the pro- (Table 2). At 2 weeks there were no significant dif-
portion of participants in whom S. aureus was isolated at ferences between POEM scores in the 2 intervention
each time point and the proportion of these swabs with groups compared with control, controlling for baseline
resistance to medications under investigation. POEM score (Table 2).
We converted data on adverse effects to a binary POEM scores at 4 weeks and 3 months, and other
variable using slight problem or worse as a cut-point, and secondary outcomes, all suggested no or minimal
we compared the odds of experiencing any adverse clinical benefit from oral or topical antibiotics (Table
effect in each of the treatment groups with those in the 2 and Supplemental Appendix 6, available at http://
control group. www.AnnFamMed.org/content/15/2/124/suppl/DC1/).
We also conducted sensitivity analyses to assess Total daily symptom scores decreased over the first
for efficacy while controlling for adherence (Complier week and then stayed relatively stable (Supplemental
Average Casual Effect [CACE]) and to assess potential Appendix 7, available at http://www.AnnFamMed.
information bias from missing data (multiple imputa- org/content/15/2/124/suppl/DC1/), and there were no
tion). A CACE analysis aims to estimate the causal significant differences in symptom scores between
effects of the intervention in those individuals who the 3 groups. There were no significant differences
ANNALS O F FAMILY MED ICINE WWW.AN N FA MME D.O R G VO L. 15, N O. 2 MA RCH/A P R IL 2017
126
ANTIBIOTICS FOR EC ZEMA
ANNALS O F FAMILY MED ICINE WWW.AN N FA MME D.O R G VO L. 15, N O. 2 MA RCH/A P R IL 2017
127
ANTIBIOTICS FOR EC ZEMA
Table 2. Effect of Oral and Topical Antibiotics on Subjective and Objective Eczema Severity at 2 Weeks,
4 Weeks, and 3 Months
EASI=Eczema Area and Severity Index (objective eczema severity); POEM=Patient Oriented Eczema Measure (subjective eczema severity).
a
Primary outcome.
Mild 19 (52.8) 8.4 (6.6) 21 (61.8) 7.0 (4.8) 15 (50.0) 7.1 (4.5)
Moderate 24 (66.7) 7.0 (4.1) 22 (64.7) 6.9 (2.8) 24 (80.0) 7.3 (3.9)
Potent 2 (5.6) 4.0 (2.8) 3 (8.8) 6.2 (5.3) 2 (6.7) 8.0 (1.4)
a
Some participants used corticosteroids of more than 1 potency, so the total number of courses exceeds the number of participants.
concealment. We found no evidence of differential use eczema, so the evidence provided by this study is of
of medications, including topical corticosteroids, and direct relevance to current practice. The mean age of
adjusting for compliance did not alter our findings. children in our study was less than 3 years, and only a
Blinded outcome assessors used well-validated instru- small number of participants were from ethnic minori-
ments to assess subjective and objective eczema sever- ties. Therefore, our results may not be generalizable to
ity at baseline and at follow-up. We achieved high rates older children or those from ethnic minorities.
of follow-up, and our primary analysis was by intention
to treat. Analysis of longer-term follow-up and analyses Comparison With Other Studies
controlling for missing data were all consistent with The only previous study to assess the effect of an
our main finding that neither topical nor oral antibiot- antibiotic in children with clinically infected eczema
ics offer any clinically important benefit. involved only 33 children and found no difference
There is no standard definition of infected eczema, between those randomized to cefadroxil and those
so we used pragmatic inclusion criteria based on randomized to placebo.25 Two further studies have
clinical suspicion of infection. Included children were examined the effects of topical antibiotics in children
clearly experiencing flares in their eczema, consider- and adults with clinically infected eczema. Both stud-
ing that their mean baseline POEM scores were higher ies reported improvements in investigator-graded
than those found in other ambulatory care stud- severity over time, and both reported significantly
ies (8.9 and 9.8 in COMET23 and BATHE24 studies better follow-up scores in those treated with combined
respectively; unpublished data), there was a significant antibiotic/steroid compared with each component indi-
improvement in severity scores during the follow-up vidually or control.26,27 Neither study, however, used
period in all groups, more than 90% had 1 or more any patient-reported or validated outcome measures,
classical signs of infection, and 70% had S. aureus iso- and neither study analyzed children separately. Two
lated from baseline swabs. Fewer than one-third, how- small trials of oral antibiotics failed to demonstrate any
ever, had moderate to severe crusting, and only 1 in 10 beneficial effect in children and adults with clinically
had moderate to severe weeping, so it is possible that uninfected eczema,28,29 and a trial of topical mupirocin
not all participants had actual infection. Nevertheless, plus hydrocortisone in 83 infants found no benefit over
all patients had what clinicians believed to be infected steroid alone in terms of the primary outcome but did
ANNALS O F FAMILY MED ICINE WWW.AN N FA MME D.O R G VO L. 15, N O. 2 MA RCH/A P R IL 2017
128
ANTIBIOTICS FOR EC ZEMA
Implications for Practice and Research Funding support: This project was funded by the National Institute for
Our data provide strong evidence that not all children Health Research Health Technology Assessment Programme (project
with clinically infected eczema need to be treated number 09/118/03).
ANNALS O F FAMILY MED ICINE WWW.AN N FA MME D.O R G VO L. 15, N O. 2 MA RCH/A P R IL 2017
129
ANTIBIOTICS FOR EC ZEMA
3. Beattie PE, Lewis-Jones MS. A comparative study of impairment of 20. Joint Formulary Committee. British National Formulary (BNF) 69. Lon-
quality of life in children with skin disease and children with other don, England:Pharmaceutical Press;2015.
chronic childhood diseases. Br J Dermatol. 2006;155(1):145-151.
21. Keogh-Brown MR, Bachmann MO, Shepstone L, et al. Contamina-
4. NHS National Institute for Health Clinical Excellence (NICE). tion in trials of educational interventions. Health Technol Assess.
National Costing Report:Atopic Eczema in Children. London, England: 2007;11(43):iii-ix107,ix-107.
NICE; 2008.
22. Francis NA, Ridd MJ, Thomas-Jones E, et al.;CREAM team. A ran-
5. Langan SM, Schmitt J, Williams HC, Smith S, Thomas KS. How are domised placebo-controlled trial of oral and topical antibiotics for
eczema flares defined? A systematic review and recommendation children with clinically infected eczema in the community:the Chil-
for future studies. Br J Dermatol. 2014;170(3):548-556. dRen with Eczema, Antibiotic Management (CREAM) study. Health
Technol Assess. 2016;20(19):i-xxiv,1-84.
6. Aagaard L, Hansen EH. Adverse drug reactions reported for sys-
temic antibacterials in Danish children over a decade. Br J Clin Phar- 23. Ridd MJ, Garfield K, Gaunt DM, et al. Choice of Moisturiser for
macol. 2010;70(5):765-768. Eczema Treatment (COMET): feasibility study of a randomised con-
trolled parallel group trial in children recruited from primary care.
7. Tott JE, van der Feltz WT, Hennekam M, van Belkum A, van
BMJ Open. 2016 Nov 16;6(11):e012021.
Zuuren EJ, Pasmans SG. Prevalence and odds of Staphylococcus
aureus carriage in atopic dermatitis:a systematic review and meta- 24. Santer M, Rumsby K, Ridd MJ, et al. Bath additives for the treat-
analysis. Br J Dermatol. 2016;175(4):687-695. ment of childhood eczema (BATHE): protocol for multicentre paral-
lel group randomized trial. BMJ Open. 2015 Nov 1;5(10):e009575.
8. Higaki S, Morohashi M, Yamagishi T, Hasegawa Y. Comparative
study of staphylococci from the skin of atopic dermatitis patients 25. Weinberg E, Fourie B, Allmann B, Toerien A. The use of cefadroxil in
and from healthy subjects. Int J Dermatol. 1999;38(4):265-269. superinfected atopic dermatitis. Curr Thera Res. 1992;52(5):671-676.
9. Birnie AJ, Bath-Hextall FJ, Ravenscroft JC, Williams HC. Interven- 26. Wachs GN, Maibach HI. Co-operative double-blind trial of an anti-
tions to reduce Staphylococcus aureus in the management of atopic biotic/corticoid combination in impetiginized atopic dermatitis. Br
eczema. Cochrane Database Syst Rev. 2008;(3):CD003871. J Dermatol. 1976;95(3):323-328.
10. Bath-Hextall FJ, Birnie AJ, Ravenscroft JC, Williams HC. Interven- 27. Larsen FS, Simonsen L, Melgaard A, Wendicke K, Henriksen
tions to reduce Staphylococcus aureus in the management of atopic AS. An efficient new formulation of fusidic acid and betametha-
eczema:an updated Cochrane review. Br J Dermatol. 2010;163(1): sone 17-valerate (fucicort lipid cream) for treatment of clinically
12-26. infected atopic dermatitis. Acta Derm Venereol. 2007;87(1):62-68.
10.2340/00015555-0174.
11. Williams HC, Burney PG, Hay RJ, et al. The U.K. Working Partys
Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a mini- 28. Ewing CI, Ashcroft C, Gibbs AC, Jones GA, Connor PJ, David TJ. Flu-
mum set of discriminators for atopic dermatitis. Br J Dermatol. 1994; cloxacillin in the treatment of atopic dermatitis. Br J Dermatol. 1998;
131(3):383-396. 138(6):1022-1029.
12. Charman CR, Venn AJ, Williams HC. The patient-oriented eczema 29. Boguniewicz M, Sampson H, Leung SB, Harbeck R, Leung DY. Effects
measure:development and initial validation of a new tool for mea- of cefuroxime axetil on Staphylococcus aureus colonization and supe-
suring atopic eczema severity from the patients perspective. Arch rantigen production in atopic dermatitis. J Allergy Clin Immunol. 2001;
Dermatol. 2004;140(12):1513-1519. 108(4):651-652.
13. Schram ME, Spuls PI, Leeflang MMG, Lindeboom R, Bos JD, 30. Canpolat F, Erkooglu M, Tezer H, Kocabas CN, Kandi B. Hydrocor-
Schmitt J. EASI, (objective) SCORAD and POEM for atopic eczema: tisone acetate alone or combined with mupirocin for atopic derma-
responsiveness and minimal clinically important difference. Allergy. titis in infants under two years of age - a randomized double blind
2012;67(1):99-106. pilot trial. Eur Rev Med Pharmacol Sci. 2012;16(14):1989-1993.
14. Gaunt DM, Metcalfe C, Ridd M. The Patient-Oriented Eczema Mea- 31. Ravenscroft JC, Layton A, Barnham M. Observations on high levels
sure in young children:responsiveness and minimal clinically impor- of fusidic acid resistant Staphylococcus aureus in Harrogate, North
tant difference. Allergy. 2016;71(11):1620-1625. Yorkshire, UK. Clin Exp Dermatol. 2000;25(4):327-330.
15. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M; 32. Hon KL, Wang SS, Lee KKC, Lee VWY, Leung TF, Ip M. Combined
EASI Evaluator Group. The eczema area and severity index (EASI): antibiotic/corticosteroid cream in the empirical treatment of moderate
assessment of reliability in atopic dermatitis. Exp Dermatol. 2001; to severe eczema:friend or foe? J Drugs Dermatol. 2012;11(7):861-864.
10(1):11-18.
33. Heng YK, Tan KT, Sen P, et al. Staphylococcus aureus and topical
16. Lewis-Jones MS, Finlay AY, Dykes PJ. The Infants Dermatitis Quality fusidic acid use:results of a clinical audit on antimicrobial resistance.
of Life Index. Br J Dermatol. 2001;144(1):104-110. Int J Dermatol. 2013;52(7):876-881.
17. Lewis-Jones MS, Finlay AY. The Childrens Dermatology Life Qual- 34. Maudsley J, Stone SP, Kibbler CC, et al. The community prevalence
ity Index (CDLQI):initial validation and practical use. Br J Dermatol. of methicillin-resistant Staphylococcus aureus (MRSA) in older peo-
1995;132(6):942-949. ple living in their own homes:implications for treatment, screening
and surveillance in the UK. J Hosp Infect. 2004;57(3):258-262.
18. Lawson V, Lewis-Jones MS, Finlay AY, Reid P, Owens RG. The family
impact of childhood atopic dermatitis: the Dermatitis Family Impact 35. Nilsson EJ, Henning CG, Magnusson J. Topical corticosteroids and
Questionnaire. Br J Dermatol. 1998;138(1):107-13. Staphylococcus aureus in atopic dermatitis. J Am Acad Dermatol.
1992;27(1):29-34.
19. Stevens KJ, Brazier JE, McKenna SP, Doward LC, Cork MJ. The devel-
opment of a preference-based measure of health in children with
atopic dermatitis. Br J Dermatol. 2005;153(2):372-377.
ANNALS O F FAMILY MED ICINE WWW.AN N FA MME D.O R G VO L. 15, N O. 2 MA RCH/A P R IL 2017
130